Using direct intraneural recordings (microneurography), I propose to extend my research on factors that modulate reflex control of muscle sympathetic nerve activity (MSNA) in humans including mental stress, somatic afferents and physical conditioning. Unique features of the work include use of microneurography to study 1) differential control of MSNA to arm and leg by cardiopulmonary and cutaneous afferents and 2) modulation of central neural sympathetic outflow during reflex stimuli such as mental stress and baroreceptor activation. I plan to evaluate these control mechanisms in normal subjects and to determine if alterations in these mechanisms contribute to abnormal reflex control in human hypertensives. First, studies are proposed to test the hypothesis that sustained stimulation of arterial baroreceptors is followed by an extended period of inhibition of MSNA even after arterial pressure has returned to control. Second, I will employ simultaneous recordings of MSNA from radial and peroneal nerves to test the hypothesis that cardiopulmonary baroreflexes produce differential control of MSNA to arm and leg. Third, we have obtained preliminary evidence for segmental activation of MSNA during somatic afferent stimulation in normal humans. These observations are intriguing in view of the concept that spinal reflexes are normally inhibited by supraspinal mechanisms. I plan simultaneous recordings from radial and peroneal nerves to test the hypothesis that cutaneous afferent stimulation (cold pressor test) produces segmental as well as generalized increases in MSNA in intact humans. Fourth, we have recently demonstrated that mental stress increases MSNA in the leg in humans. I plan to test the hypothesis that endogenous opioids inhibit and beta adrenergic mechanisms facilitate increases in central neural sympathetic outflow during mental stress. Fifth, our recent work suggests that activation of chemically sensitive muscle afferents by muscle ischemia is the principal stimulus to MSNA during exercise. Physical conditioning minimizes muscle ischemia. I therefore intend to test the hypothesis that physical conditioning will attenuate MSNA responses to exercise. Microneurographic recordings of MSNA are safe and provide a substantial advance for studies of reflex control in humans.